Azaheterocyclymethyl-chromans

ABSTRACT

Azaheterocyclylmethyl-chromans of the formula: ##STR1## in which E represents an azaheterocyclyl group selected from the group consisting of: ##STR2## wherein R 6  represents hydrogen, hydroxyl, halogen or phenyl; and 
     n represents an integer 0-8; 
     and the other substituents are as defined herein; 
     or an optically isomeric form thereof or a salt thereof; 
     are useful to treat anxiety, depression and psychoses.

This application is a divisional, of application Ser. No. 08/292,639,filed Aug. 18, 1994 U.S. Pat. No. 5,545,643; which is a divisional ofSer. No. 07/984,076, filed Nov. 30, 1992, issued to U.S. Pat. No.5,371,094.

This invention relates to azaheterocyclylmethyl-chromans, processes fortheir preparation and their use in medicaments, in particular as agentsfor controlling diseases of the central nervous system.

It is already known that 2-benzofuranylmethyl derivatives have anactivity on the central nervous system (compare German PatentSpecification DE 2 165 276).

In addition, the compound 1-(3,4-dihydro-2H-1-benzopyran-2-yl)methyl!piperidine in the form of itshydrochloride having an α-adrenergic-blocking effect is described in thepublication Eur. J. Med. Chem. 22 (6), 539-544.

The invention relates to azaheterocyclylmethyl-chromans of the generalformula (I), ##STR3## in which A, B and D independently of one anotherrepresent hydrogen, halogen, cyano, azido, nitro, difluoromethyl,trifluoromethyl, difluoromethoxy, trifluoromethoxy, hydroxyl orcarboxyl, or

represent straight-chain or branched alkyl, alkenyl, acyl oralkoxycarbonyl having, in each case, up to 8 carbon atoms, or

represent a group of the formula --NR¹ R², --NR³ --L--R⁴ or --OR⁵,

wherein

R¹, R² and R³ are identical or different and denote hydrogen,straight-chain or branched alkyl having up to 8 carbon atoms, phenyl orbenzyl,

L denotes the --CO-- or --SO₂ -- group,

R⁴ denotes straight-chain or branched alkyl having up to 8 carbon atomsor benzyl, or denotes aryl having 6 to 10 carbon atoms, which isoptionally substituted by halogen, hydroxyl, nitro, cyano,trifluoromethyl or trifluoromethoxy or by straight-chain or branchedalkyl or alkoxy having up to 6 carbon atoms, and

R⁵ denotes straight-chain or branched alkyl or alkenyl having, in eachcase, up to 8 carbon atoms, which are optionally substituted bycycloalkyl having 3 to 6 carbon atoms or phenyl,

or

A has one of the abovementioned meanings and

B and D together with the aromatic radical form a 5-membered to7-membered saturated, partially unsaturated or aromatic carbocycle orheterocycle having up to 2 hetero atoms from the series S, N or O, thesaid cyclic radicals optionally being able to have up to 2 carbonylfunctions in the ring and optionally being substituted, by up to 2identical or different substituents, by straight-chain or branchedalkyl, alkenyl or alkoxy having, in each case, up to 6 carbon atoms,hydroxyl, cycloalkyl having 3 to 6 carbon atoms, phenyl, halogen, cyanoor nitro or, in a spiro-like manner, by a radical of the formula##STR4## wherein m denotes a number 1 or 2, and

E represents a heterocyclic radical of the formula ##STR5## wherein R⁶denotes hydrogen, hydroxyl, halogen or phenyl,

R⁷ and R⁸ independently of one another denote a straight-chain orbranched alkyl having up to 8 carbon atoms, which must be substituted bya radical of the formula ##STR6## or denote a radical of the formula##STR7## and R⁹ denotes hydrogen, halogen, cyano, nitro,trifluoromethyl, trifluoromethoxy, hydroxyl or straight-chain orbranched alkyl or alkoxy having, in each case, up to 6 carbon atoms,

optionally in an isomeric form,

and their salts.

Within the framework of the present invention, physiologicallyacceptable salts are preferred. Physiologically acceptable salts of thecompounds according to the invention can be salts of the substancesaccording to the invention with inorganic acids, carboxylic acids orsulphonic acids. Particularly preferred salts are, for example, saltswith hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoricacid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonicacid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid,propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid,maleic acid or benzoic acid.

Heterocycle in general represents a 5-membered to 7-membered, preferably5-membered to 6-membered, saturated or unsaturated ring, which cancontain up to 2 oxygen, sulphur and/or nitrogen atoms as hetero atoms.5-membered and 6-membered rings containing one oxygen, sulphur and/or upto 2 nitrogen atoms are preferred. The following are preferablymentioned: thienyl, furyl, pyrrolyl, pyrazolyl, pyranyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl, oxazolyl, imidazolyl,isoxazolyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrazolyl,morpholinyl or dioxanyl.

Within the framework of the present invention the compounds according tothe invention can be present in various stereoisomeric forms. Thecompounds according to the invention exist in stereoisomeric forms whichare either related to one another as image and mirror image(enantiomers) or are not related to one another as image and mirrorimage (diastereoisomers). The invention relates both to the antipodesand the racemic forms and to the mixtures of diastereoisomers. Theracemic forms can be separated in the same way as the diastereoisomersin a known manner into the single stereoisomer constituents compare E.L. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962!.

Preferred compounds of the general formula (I) are those in which

A, B and D independently of one another represent hydrogen, fluorine,chlorine, bromine, cyano, trifluoromethyl, difluoromethoxy,trifluoromethoxy or hydroxyl, or represent straight-chain or branchedalkyl, alkenyl, acyl or alkoxycarbonyl having, in each case, up to 6carbon atoms, or represent a group of the formula --NR¹ R², --NR³--L--R⁴ or --OR⁵,

wherein

R¹, R² and R³ are identical or different and denote hydrogen orstraight-chain or branched alkyl having up to 6 carbon atoms,

L denotes the --CO-- or --SO₂ -- group,

R⁴ denotes straight-chain or branched alkyl having up to 6 carbon atomsor benzyl, or denotes phenyl which is optionally substituted byfluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy orhydroxyl or by straight-chain or branched alkyl or alkoxy having, ineach case, up to 4 carbon atoms, and

R⁵ denotes straight-chain or branched alkyl or alkenyl having up to 6carbon atoms, which are optionally substituted by cyclopropyl,cyclopentyl, cyclohexyl or phenyl,

or

A has one of the abovementioned meanings and

B and D together form a radical of the formula ##STR8## and E representsa heterocyclic radical of the formula ##STR9## wherein R⁶ denoteshydrogen, hydroxyl, fluorine, chlorine, bromine or phenyl,

R⁷ and R⁸ independently of one another denote straight-chain or branchedalkyl having up to 6 carbon atoms, which must be substituted by aradical of the formula ##STR10## or denote a radical of the formula##STR11## and R⁹ denotes hydrogen, fluorine, chlorine, bromine,trifluoromethyl, hydroxyl or straight-chain or branched alkyl or alkoxyhaving, in each case, up to 4 carbon atoms,

optionally in an isomeric form,

and their salts.

Particularly preferred compounds of the general formula (I) are those inwhich

A, B and D independently of one another represent hydrogen, fluorine,chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy or hydroxyl,or

represent straight-chain or branched alkyl or alkenyl having, in eachcase, up to 4 carbon atoms, or

represent a group of the formula --NR¹ R² or --OR⁵,

wherein

R¹ and R² are identical or different and denote hydrogen orstraight-chain or branched alkyl having up to 4 carbon atoms, and

R⁵ denotes straight-chain or branched alkyl or alkenyl having up to 4carbon atoms, which are optionally substituted by cyclopropyl or phenyl,

or

A has one of the abovementioned meanings and

B and D together form a radical of the formula ##STR12## E represents aheterocyclic radical of the formula ##STR13## wherein R⁶ denoteshydrogen, hydroxyl, fluorine or chlorine,

R⁷ and R⁸ independently of one another denote straight-chain or branchedalkyl having up to carbon atoms, which must be substituted by a radicalof the formula ##STR14## or denote a radical of the formula ##STR15##and R⁹ denotes hydrogen, fluorine, chlorine, trifluoromethyl, hydroxyl,methyl, ethyl, methoxy or ethoxy,

optionally in an isomeric form,

and their salts.

In addition, processes for the preparation of the compounds according tothe invention of the general formula (I) have been found, characterisedin that

A! Compounds of the general formula (II) ##STR16## in which A, B and Dhave the abovementioned meaning and

Y represents hydroxyl or represents a typical leaving group, such as,for example, tosylate, chloride or mesylate, preferably tosylate,

are reacted directly with compounds of the general formula (III)

    H--E                                                       (III),

in which

E has the abovementioned meaning,

in inert solvents, in the presence of a base and optionally of anauxiliary (catalyst, starter), or

B! in the case where R⁷ represents a radical of the formula --T--R¹⁰,

wherein

T denotes straight-chain or branched alkyl having up to 8 carbon atomsand

R¹⁰ represents one of the heterocyclic radicals mentioned above underR⁷,

compounds of the general formula (IV), ##STR17## in which A, B, D, R⁶and T have the abovementioned meaning,

are reacted with compounds of the general formula (V)

    H--R.sup.10                                                (V)

in which

R¹⁰ has the abovementioned meaning,

in inert solvents in a Mitsunobu reaction,

and, optionally, reductions are carried out by conventional methods, and

in the case of the enantiomers, either the compounds of the generalformula (III) are reacted with compounds of the general formula (II)which are in the form of a single enantiomer, or the correspondingracemates of the compounds of the general formula (I) are separated bythe known methods for racemate separation described above, for exampleby separation via salts with acids in the form of a single enantiomer,

and, optionally, the substituents A, B and D are converted toderivatives, likewise by known methods.

The processes according to the invention can be illustrated by way ofexample by the following equation: ##STR18##

Suitable solvents for the reaction with the amines of the generalformula (III) are the conventional solvents which do not change underthe reaction conditions. These preferably include alcohols, such asmethanol, ethanol, propanol or isopropanol, or ethers, such as diethylether, dioxane, tetrahydrofuran, glycol dimethyl ether or butyl methylether, or ketones, such as acetone or butanone, or amides, such asdimethylformamide or hexamethylphosphoric acid triamide, ordimethylsulphoxide, acetonitrile, ethyl acetate or halogenatedhydrocarbons, such as methylene chloride, chloroform or carbontetrachloride, or pyridine, picoline or N-methylpiperidine. Mixtures ofthe said solvents can also be used. Methanol, ethanol, propanol,isopropanol or dimethylformamide are preferred.

Suitable bases are the conventional inorganic or organic bases. Thesepreferably include alkali metal hydroxides, such as sodium hydroxide orpotassium hydroxide, or alkali metal carbonates, such as sodiumcarbonate or potassium carbonate, or alkali metal alcoholates, such as,for example, sodium methanolate, potassium methanolate, sodiumethanolate or potassium ethanolate, or organic amines, such astriethylamine, picoline, pyridines or N-methylpiperidine, or amides,such as sodium amide or lithium diisopropylamide. Sodium carbonate,potassium carbonate and pyridine are preferred.

The bases are used in an amount of 0.5 mol to 10 mols, preferably of 0.3mol to 3 mols, based on 1 mol of the compounds of the general formula(II). In the case of pyridine, the base can also be used as solvent.

The reaction is generally carried out in a temperature range of 0° C. to150° C., preferably of +20° C. to +110° C.

The reaction can be carried out under normal, elevated or reducedpressure (for example 0.5 to 5 bar). In general the reaction is carriedout under normal pressure.

The reductions can in general be carried out by hydrogen in water or ininert organic solvents, such as alcohols, ethers or halogenatedhydrocarbons, or mixtures thereof, using catalysts such as Raney nickel,palladium, palladium-on-animal charcoal or platinum, or using hydridesor boranes in inert solvents, if appropriate in the presence of acatalyst.

The reaction is preferably carried out using hydrides, such as complexborohydrides or aluminium hydrides. In this context, sodium borohydride,lithium aluminium hydride or sodium cyanoborohydride are particularlypreferably employed.

Suitable solvents in this context are all inert organic solvents whichdo not change under the reaction conditions. These preferably includealcohols, such as methanol, ethanol, propanol or isopropanol, or ethers,such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl etheror diethylene glycol dimethyl ether, or amides, such ashexamethylphosphoric acid triamide or dimethylformamide, or acetic acid.It is also possible to use mixtures of the said solvents.

The catalysts used in the reduction with sodium cyanoborohydride are ingeneral protic acids. These preferably include inorganic acids, such as,for example, hydrochloric acid or sulphuric acid, or organic carboxylicacids having 1-6 C atoms, optionally substituted by fluorine, chlorineand/or bromine, such as, for example, acetic acid, trifluoroacetic acid,trichloroacetic acid or propionic acid, or sulphonic acids containing C₁-C₄ -alkyl radicals or aryl radicals, such as, for example,methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid ortoluenesulphonic acid.

The Mitsunobu reaction generally proceeds in one of the non-proticsolvents indicated above, preferably tetrahydrofuran, in the presence ofphosphanes, preferably triphenylphosphane, and ester derivatives ofazodicarboxylic acid, preferably diethyl azodicarboxylate, in atemperature range of 0° C. to +50° C., preferably at room temperatureand normal pressure in this context compare O. Mitsunobu, Synthesis1981,1!.

The compounds of the general formula (II) are known per se or can beprepared by conventional methods compare German Patent Specification 3620 408 A, U.S. Pat. No. 4,957,928, Farmaco, Ed. Sci. 42 (11), 805-813!,it being possible to obtain compounds in the form of a single enantiomerby using the corresponding chroman-2-carboxylic acids in the form of asingle enantiomer and their derivatives for the preparation in thiscontext compare J. Labelled Comp. Pharm. 24, 909, 1987!.

The amines of the general formula (III) are known, can be prepared byconventional methods or are available commercially compare MSD Book 2,2846 D; Beilstein 21 (2) 8!.

The majority of the compounds of the general formula (IV) are novel andcan then be prepared, for example, by reducing in inert solvents, thecorresponding compounds of the general formula (VI) ##STR19## in whichA, B, D and R⁶ have the abovementioned meaning and

R¹¹ represents C₁ -C₄ -alkyl.

The reduction of the acid amides and imides is effected using hydridesin inert solvents or using boranes, diboranes or their complexcompounds.

The reactions are preferably carried out using hydrides, such as complexborohydrides or aluminium hydrides, as well as boranes. In this context,sodium borohydride, lithium aluminium hydride, sodiumbis-(2-methoxyethoxy)aluminium hydride or borane-tetrahydrofuran areparticularly preferably employed.

The reaction can be carried out under normal, elevated or reducedpressure (for example 0.5 to 5 bar). In general the reaction is carriedout under normal pressure.

The reduction is in general effected in a temperature range of -50° C.up to the boiling point of the particular solvent, preferably of -20° C.to +90° C.

The compounds of the general formula (VI) are known in some cases or arenovel and can be prepared, for example, by reacting the correspondingactivated chroman-2-carboxylic acid derivatives withpiperidine-4-carboxylic acid esters in inert solvents, preferablypyridine, in the presence of one of the abovementioned bases, preferablypyridine.

The compounds according to the invention can be used as active compoundsin medicaments. The substances according to the invention have aparticularly high affinity for cerebral 5-hydroxy-tryptamine receptorsof the 5-HT₁ type. They also have high affinity for dopamine receptorsof the D₂ type.

The substances according to the invention surprisingly show anadvantageous effect on the central nervous system and can be used forthe therapeutic treatment of humans and animals.

The compounds described in the present invention are thus activecompounds for controlling diseases which are characterised by disordersof the serotoninergic and dopaminergic system, in particular in the caseof the involvement of receptors which have high affinity for5-hydroxytryptamine (5-HT₁ type) and/or for dopamine (D₂ type). They aretherefore suitable for the treatment of diseases of the central nervoussystem, such as anxiety, stress and depressive states, sexualdysfunctions related to the central nervous system and sleep disorders,and for regulating pathological disorders of food, coffee, tea, tobacco,alcohol and addictive drug intake. They are also suitable for theelimination of cognitive deficits, for the improvement of learning andmemory performance and for the treatment of Alzheimer's disease. Theyare also suitable for controlling psychoses (for example schizophrenia,mania). Compared with known neuroleptic agents, they have a lowerpotential for side effects.

Furthermore, these active compounds are also suitable for modulation ofthe cardiovascular system. They also intervene in regulation of thecerebral circulation and are thus effective agents for controllingmigraine.

They are also suitable for the prophylaxis and control of theconsequences of cerebral infarct events (apoplexia cerebri), such asstroke and cerebral ischaemias. Moreover, the compounds can be used forthe treatment of acute craniocerebral trauma. The compounds according tothe invention can also be used to control states of pain.

Affinity for the 5-HT₁ Receptor

The high affinity of the compounds according to the invention for5-hydroxytryptamine receptors of subtype 1 is shown in Table 1 by way ofexample. The values shown are data which have been determined fromreceptor-binding studies using calf hippocampus membrane preparations.To this end, ³ H-serotonin was used as radioactively labelled ligand.

                  TABLE A                                                         ______________________________________                                        Compound of Example                                                                            K.sub.i (nmol/l)                                             ______________________________________                                        2                3                                                            4                2                                                            ______________________________________                                    

Affinity for the 5-HT_(1A) Receptor

W. U. Dompert et al., Naunyn-Schmiedeberg's Arch. Pharmacol. (1985),328, 467-470!.

In this test the binding of ³ H-ipsapiron to 5-HT_(1A) receptors in calfhippocampus membranes is measured. It was found that the compoundsaccording to the invention compete for the binding with the radioligandand inhibit them.

                  TABLE B                                                         ______________________________________                                        Compound of Example                                                                            K.sub.i (nmol/l)                                             ______________________________________                                        5                1.5                                                          6                1.4                                                          ______________________________________                                    

Dopamine D₂ Receptor Test

This test is carried out in accordance with the following literaturereference: Imafuku J. (1987), Brain Research 402; 331-338.

In this test the binding of the selective D, receptor antagonist ³H-sulpiride to membranes from the striatum of rats is measured.Compounds which bind to dopamine D₂ receptors inhibit the binding of ³H-sulpiride in a concentration-dependent manner. IC₅₀ values aredetermined from the displacement curves and the inhibition constantsK_(i) calculated from these values.

                  TABLE C                                                         ______________________________________                                        Compound of Example                                                                            K.sub.i (nmol/l)                                             ______________________________________                                        2                1.8                                                          3                0.4                                                          6                2.3                                                          ______________________________________                                    

The present invention also includes pharmaceutical preparations whichcontain, in addition to inert, non-toxic, pharmaceutically suitableauxiliaries and excipients, one or more compounds of the general formula(I), or which consist of one or more active compounds of the formula(I), as well as processes for the production of these preparations.

The active compounds of the formula (I) should be present in thesepreparations in a concentration of 0.1 to 99.5% by weight and preferablyof 0.5 to 95% by weight of the total mixture.

In addition to the active compounds of the formula (I), thepharmaceutical preparations can also contain other pharmaceutical activecompounds.

The abovementioned pharmaceutical preparations can be prepared in aconventional manner by known methods, for example using the auxiliary orauxiliaries or excipient(s).

In general, it has proved advantageous to administer the active compoundor active compounds of the formula (I) in total amounts of about 0.01 toabout 100 mg/kg, preferably in total amounts of about 1 mg/kg to 50mg/kg of body weight per 24 hours, optionally in the form of severalsingle doses, in order to achieve the desired results.

However, it can, where appropriate, be advantageous to deviate from thesaid amounts and specifically to do so as a function of the nature andthe body weight of the object to be treated, of the individual behaviourtowards the medicament, the nature and severity of the disease, the typeof preparation and application and the time or interval at whichadministration takes place.

Unless indicated otherwise, the R_(f) values mentioned in each case weredetermined by thin layer chromatography on silica gel (aluminium foil,silica gel 60 F 254, E. Merck). The substance spots were visualised byobserving under UV light and/or by spraying with 1% strength potassiumpermanganate solution.

Flash chromatography was carried out on silica gel 60, 0.040-0.064 mm,E. Merck (see Still et al., J. Org. Chem. 43, 2923, 1978: for simplerseparation problems see Aldrichimica Acta 18, 25, 1985). Elution usingsolvent gradients denotes: Starting with the pure, nonpolar solventmixture component, the polar eluent component is admixed in anincreasing proportion until the desired product is eluted (TLC control).

For all products, the solvent was distilled off under, finally, about0.1 mmHg. Salts were stored under this pressure overnight over potassiumhydroxide and/or phosphorus pentoxide.

STARTING COMPOUNDS Example I 8-Methoxy-chroman-2-carboxylic Acid(4-ethoxycarbonyl)piperidide ##STR20##

9.0 g (40 mmol) of 8-methoxy-chroman-2-carboxylic acid chloride areadded in several portions to 6.3 g of ethyl piperidine-4-carboxylate (40mmol) and 0.1 g of 4-dimethylaminopyridine in 20 ml of anhydrouspyridine. After 40 hours at room temperature, the mixture is poured ontoice. The solid which precipitates after 30 minutes is washed with waterand dried in a desiccator.

Yield: 6.2 g (45%)

This material is further used without further purification.

Example II 2-Hydroxymethyl-8-methoxy-chroman ##STR21##

59.0 g (0.25 mol) of ethyl 8-methoxy-chroman-2-carboxylate in 525 ml ofanhydrous tetrahydrofuran are added dropwise in the course of 1 h, withstirring, at 20° C. to a suspension of 9.5 g (0.25 mol) of lithiumaluminium hydride in 525 ml of anhydrous diethyl ether. The batch isstirred overnight and 9.5 ml of water, 9.5 ml of 15% strength sodiumhydroxide solution and 28.4 ml of water are then successively addeddropwise, with cooling. The organic phase is decanted off andevaporated. The residue is recrystallised twice fromdichloromethane/petroleum ether.

Yield: 38.0 g (87%)

Melting point: 57°-58° C.

Example III (2R )-2-Hydroxymethyl-chroman ##STR22##

164 ml of a 1M solution of borane in tetrahydrofuran is added dropwisein the course of 30 minutes to a solution of 22.1 g (0.124 mol) of(2R)-chroman-2-carboxylic acid (ee=98.3%) in 210 ml of anhydroustetrahydrofuran under argon, at an internal temperature of 0° C. Thecooling is removed and the batch is stirred for a further 4 h. Theinternal temperature rises during this period to 34° C. 46 ml of a 1/1mixture of tetrahydrofuran and water are then added dropwise, with icecooling. After adding 40.7 g of anhydrous potassium carbonate andstirring vigorously, the tetrahydrofuran solution is decanted andconcentrated under a water pump vacuum. Short-path distillation yields18.8 g of colourless 2R-hydroxymethyl-chroman having a boiling point of77°-78° C./0.15 mbar. ee >99%.

Example IV (2S)-2-Hydroxymethyl-chroman ##STR23##

The title compound is prepared from (2S)-2-chroman-2-carboxylic acidanalogously to the method of Example II.

ee >99%

Boiling point: 79°-81° C./0.15 mbar

Example V (2R)-2-Tosyloxymethyl-chroman ##STR24##

15.63 g (0.082 mol) of 4-toluenesulphonyl chloride are added in portionsto 12.8 g (0.078 mol) of (2R)-2-hydroxymethylchroman (Example II) in 50ml of anhydrous pyridine, with stirring and ice cooling. After leavingto stand overnight, the batch is introduced into ice-water and extractedwith diethyl ether. The ether phase is washed twice with 5% strengthice-cold hydrochloric acid and then with saturated sodium chloridesolution, dried over anhydrous sodium sulphate and evaporated under awater pump vacuum. 22.4 g of 2R-2-hydroxymethylchroman4-toluenesulphonate in the form of a single compound are obtained.

R_(f) =0.6 (toluene/ethyl acetate 3:1) oil

Melting point: 62°-65° C. (petroleum ether/dichloromethane)

α!_(D) =51.1° (c=1, chloroform)

Example VI (2S)-2-Tosyloxymethyl-chroman ##STR25##

The title compound from Example III is prepared analogously to themethod of Example IV.

R_(f) =0.6 (toluene/ethyl acetate 3:1) oil

Example VII 8-Methoxy-2-tosyloxymethyl-chroman ##STR26##

Melting point: 115°-117° C. (from dichloromethane)

Example VIII 2-Phthalimidomethyl-8-methoxy-chroman ##STR27##

By reacting the compound from Example II with phthalimide in thepresence of equimolar amounts of triphenylphosphane and diethylazodicarboxylate in tetrahydrofuran, the desired product is obtained in80% yield in the form of a syrup, which is further reacted directly.

R_(f) =0.46 (toluene/ethyl acetate 3:1)

Example IX 2- (4-Hydroxymethyl)-piperidin-1-yl!methyl-8-methoxy-chromanHydrochloride ##STR28##

31 ml of a 3.4M solution of sodiumbis-(2-methoxyethoxy)-dihydroaluminate in toluene are added to 5.2 g (15mmol) of the compound from Example I in 31 ml of toluene and the mixtureis stirred for 18 h at 50° C. under argon. After dilution with toluene,the reaction mixture is hydrolysed with 10 ml of 1:1 mixture oftetrahydrofuran and water. Filtration and flash chromatography of thefiltrate (silica gel, toluene/i-propanol--gradient 100:0 to 50:50)yields the product in the form of the free base; 2.8 g (64%) in the formof a syrup. By treatment with ethereal hydrochloric acid, thehydrochloride is obtained, which is recrystallised from acetonitrile.

Melting point: 107°-112° C. (after recrystallisation from acetonitrile)

IR (KBr): 3510, 3301(b), 2945, 2548(b), 1630(w), 1583(w), 1481

The compounds listed in Table I are prepared analogously to the methodsof Examples I and IX:

                  TABLE I                                                         ______________________________________                                         ##STR29##                                                                                                         Preparation                                                                   analogous to                             Ex. No.                                                                              X        Y          m.p. °C.                                                                         Example                                  ______________________________________                                        X      CO       CO.sub.2 C.sub.2 H.sub.5                                                                 64-66     I                                                                   (from petroleum                                                               ether/ether)                                       XI     CH.sub.2 CH.sub.2 OH                                                                              oil       IX                                       ______________________________________                                    

PREPARATION EXAMPLES Example 12-(1H-2,3-dihydro-2-indol-2-yl)methyl-8-methoxychroman Hydrochloride##STR30##

7.3 g (23 mmol) of the compound from Example VIII in 50 ml oftetrahydrofuran are added dropwise to 2.5 g (68 mmol) of lithiumaluminium hydride in 80 ml of diethyl ether. The mixture is refluxed for5 hours and then left to stand for 15 hours at room temperature. 10 mlof water in 30 ml of tetrahydrofuran, followed by 5 ml of 45% sodiumhydroxide solution are added dropwise. After filtering throughkieselguhr and rinsing the solid with toluene/ethyl acetate 1/1, afiltrate is obtained which is concentrated in a rotary evaporator. Flashchromatography (silica gel, toluene/ethyl acetate gradient 100:0 to75:25) yields 6.2 g (93%) of the desired product in the form of the freebase (syrup). The hydrochloride is obtained from this base by treatmentwith ethereal hydrochloric acid.

Melting point: 256°-258° C. (after recrystallisation from 2-propanol)

R_(f) =0.35 (silica gel, toluene/ethyl acetate 1:1)

MS (EI): 295, 132 (100%), 105, 36

Example 2 2-4-(Isoindol-1,3-dion-2-yl)methyl-piperidin-1-yl)methyl-8-methoxychromanOxalate Hydrate ##STR31##

4.1 g (14 mmol) of the compound from Example IX, 4.1 g (15 mmol) oftriphenylphosphine and 2.3 g (15 mmol) of phthalimide are dissolved in 6ml of dry tetrahydrofuran. 2.7 g of diethyl azodicarboxylate in 10 ml oftetrahydrofuran are added dropwise to this solution at room temperature.After 10 days at room temperature, the reaction mixture is concentratedand the residue digested with cyclohexane. Insoluble matter is filteredoff and the filtrate is concentrated in a rotary evaporator.Chromatography (silica gel, toluene/ethyl acetate 100:0 to 50:50) andrechromatography (silica gel, dichloromethane/2-propanol 50:1 to 10:1)yields the desired product in the form of an oil (1.15 g). Thehydrochloride (1.15 g, 16%) is precipitated from this oil by treatmentwith ethereal hydrochloric acid. For further purification, the base isliberated from the hydrochloride using sodium bicarbonate solution. Theoxalate, which is accessible by adding oxalic acid dihydrate inethanolic solution, is recrystallised from acetonitrile. Furtherrecrystallisation from 2-propanol yields 0.30 g of analytically puretitle compound after cooling to -36° C.

Melting point: >70° C. (decomposition)

R_(f) =0.3 (silica gel, dichloromethane/2-propanol 20:1)

Example 3 1-(Chroman-2-yl-methyl)-4-(2-oxo-1-benzimidazolyl)piperidine##STR32##

The mixture of 8.8 g (27.7 mmol) of (chroman-2R,S-yl-methyl)4-toluenesulphonate, 2.1 g (20 mmol) of anhydrous sodium carbonate and6.5 g (30 mmol) of 4-(2-oxo-1-benzimidazolinyl)-piperidine in 70 ml ofanhydrous dimethylformamide is stirred for 6 h at 110° C. and thenpoured onto ice (250 g). After extracting with ethyl acetate, washingthe organic extracts with water, drying over anhydrous sodium sulphateand evaporating the organic phase under a water pump vacuum, 9.8 g ofcrystalline crude product which is virtually a single compound areobtained, which product is twice recrystallised fromdichloromethane/petroleum ether for analysis.

Melting point: 107°-109° C. (cap.)

The examples listed in Tables 1 and 2 were prepared analogously to themethod of Example 3.

                  TABLE 1                                                         ______________________________________                                         ##STR33##                                                                    Ex. No.                                                                             A        B     E                m.p. °C.                         ______________________________________                                        4     OCH.sub.3                                                                              H                                                                                    ##STR34##       196-197 (free base)                     5     H        H                                                                                    ##STR35##       138-140 (free base)                     6     OCH.sub.3                                                                              H                                                                                    ##STR36##       167-169 (free base)                     ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                         ##STR37##                                                                    Ex.                                                                           No.  Z                     m.p. °C.                                    ______________________________________                                              ##STR38##            167-168 (free base) α.sub.D = -51.2 (c =                                0.6, THF)                                          8                                                                                   ##STR39##            167-168 α.sub.D = +53.9 (c = 0.6,            ______________________________________                                                                   THF)                                           

We claim:
 1. An azaheterocyclylmethyl-chroman of the formula: ##STR40##in which A, B and D independently of one another represent hydrogen,halogen, cyano, azido, nitro, difluoromethyl, trifluoromethyl,difluoromethoxy, trifluoromethoxy or carboxyl; orrepresentstraight-chain or branched alkyl, alkenyl, alkanoyl or alkoxycarbonylhaving in each case up to 8 carbon atoms; or represent a group of theformula --NR¹ R², --NR³ --L--R⁴ or --OR⁵ ; whereinR¹, R² and R³ areidentical or different and represent hydrogen, straight-chain orbranched alkyl having up to 8 carbon atoms, phenyl or benzyl; Lrepresents --CO-- or --SO₂ --; R⁴ represents straight-chain or branchedalkyl having up to 8 carbon atoms or benzyl, or represents hydrocarbylaryl having 6-10 carbon atoms, which is optionally substituted byhalogen, hydroxyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, orby straight-chain or branched alkyl or alkoxy having up to 6 carbonatoms; R⁵ represents straight-chain or branched alkenyl having up to 8carbon atoms, which is optionally substituted by cycloalkyl having 3 to6 carbon atoms or phenyl, or represents straight-chain or branched alkylhaving up to 8 carbon atoms, which is substituted by cycloalkyl having 3to 6 carbon atoms or phenyl;or A has one of the abovementioned meanings;and B and D together form a radical of the formula: ##STR41## Erepresents a heterocyclic radical of the formula ##STR42## wherein R⁶denotes hydrogen, hydroxyl, fluorine, chlorine, bromine or phenyl,R⁷denotes straight-chain or branched alkyl having up to 6 carbon atoms,which must be substituted by a radical of the formula ##STR43## ordenotes a radical of the formula ##STR44## or E represents aheterocyclic radical of the formula ##STR45## wherein R⁸ denotesstraight-chain or branched alkyl having up to 6 carbon atoms, which mustbe substituted by a radical of the formula ##STR46## or denotes aradical of the formula ##STR47## and R⁹ denotes hydrogen, fluorine,chlorine, bromine, trifluoromethyl, hydroxyl or straight-chain orbranched alkyl or alkoxy having, in each case, up to 4 carbon atoms,oran optically active isomeric form thereof or a salt thereof.
 2. Anazaheterocyclylmethyl-chroman of the formula: ##STR48## in which A, Band D independently of one another represent hydrogen, halogen, cyano,azido, nitro, difluoromethyl, trifluoromethyl, difluoromethoxy,trifluoromethoxy or carboxyl; orrepresent straight-chain or branchedalkyl, alkenyl, alkanoyl or alkoxycarbonyl having in each case up to 8carbon atoms; or represent a group of the formula --NR¹ R², --NR³--L--R⁴ or --OR⁵ ; whereinR¹, R² and R³ are identical or different andrepresent hydrogen, straight-chain or branched alkyl having up to 8carbon atoms, phenyl or benzyl; L represents --CO-- or --SO₂ --; R⁴represents straight-chain or branched alkyl having up to 8 carbon atomsor benzyl, or represents hydrocarbyl aryl having 6-10 carbon atoms,which is optionally substituted by halogen, hydroxyl, nitro, cyano,trifluoromethyl, trifluoromethoxy, or by straight-chain or branchedalkyl or alkoxy having up to 6 carbon atoms; R⁵ representsstraight-chain or branched alkenyl having up to 8 carbon atoms, which isoptionally substituted by cycloalkyl having 3 to 6 carbon atoms orphenyl, or represents straight-chain or branched alkyl having up to 8carbon atoms, which is substituted by cycloalkyl having 3 to 6 carbonatoms or phenyl;or A has one of the abovementioned meanings; and B and Dtogether form a radical of the formula: ##STR49## R⁶ representshydrogen, hydroxyl, halogen or phenyl; an optically isomeric formthereof or a salt thereof.
 3. The azaheterocyclylmethyl-chromanaccording to claim 2, whereinA, B and D independently of one anotherrepresent hydrogen, fluorine, chlorine, bromine, cyano, trifluoromethyl,difluoromethoxy or trifluoromethoxy; or represent straight-chain orbranched alkyl, alkenyl, alkanoyl or alkoxycarbonyl having in each caseup to 6 carbon atoms; or represent a group of the formula --NR¹ R²,--NR³ --L--R⁴ or --OR⁵ ; whereinR¹, R² and R³ are identical or differentand represent hydrogen or straight-chain or branched alkyl having up to6 carbon atoms; L represents --CO-- or --SO₂ --; R⁴ representsstraight-chain or branched alkyl having up to 6 carbon atoms or benzyl,or represents phenyl, which is optionally substituted by fluorine,chlorine, bromine, hydroxyl, trifluoromethyl, trifluoromethoxy, or bystraight-chain or branched alkyl or alkoxy having up to 4 carbon atoms;R⁵ represents straight-chain or branched alkenyl having up to 6 carbonatoms, which is optionally substituted by cyclopropyl, cyclopentyl,cyclohexyl or phenyl, or represents straight-chain or branched alkylhaving up to 6 carbon atoms, which is substituted by cyclopropyl,cyclopentyl, cyclohexyl or phenyl;or A has one of the abovementionedmeanings; and B and D together form a radical of the formula: ##STR50##R⁶ represents hydrogen, hydroxyl, fluorine, chlorine, bromine orphenyl;an optically isomeric form thereof or a salt thereof.
 4. Theazaheterocyclylmethyl-chroman according to claim 2, whereinA, B and Dindependently of one another represent hydrogen, fluorine, chlorine,bromine, cyano, trifluoromethyl or trifluoromethoxy; or representstraight-chain or branched alkyl or alkenyl having in each case up to 4carbon atoms; or represent a group of the formula --NR¹ R² or --OR⁵ ;whereinR¹ and R² are identical or different and represent hydrogen orstraight-chain or branched alkyl having up to 4 carbon atoms; R⁵represents straight-chain or branched alkenyl having up to 4 carbonatoms, which is optionally substituted by cyclopropyl or phenyl, orrepresents straight-chain or branched alkyl having up to 4 carbon atoms,which is substituted by cyclopropyl or phenyl;or A has one of theabovementioned meanings; and B and D together form a radical of theformula: ##STR51## R⁶ represents hydrogen, hydroxyl, fluorine orchlorine; an optically isomeric form thereof or a salt thereof.
 5. Acompound according to claim 2, wherein such compound is1-(chroman-2-yl-methyl)-4-(2-oxo-1-benzimidazolyl)-piperidine of theformula: ##STR52## or a salt thereof.
 6. A compound according to claim2, wherein such compound is(+)-1-(chroman-2-yl-methyl)-4-(2-oxo-1-benzimidazolyl)-piperidine or asalt thereof.
 7. A compound according to claim 2, wherein such compoundis (-)-1-(chroman-2-yl-methyl)-4-(2-oxo-1-benzimidazolyl)-piperidine ora salt thereof.
 8. The compound 1-(8-methoxy-chroman-2-yl)-methyl!-4-(2-oxo-1-benzimidazolyl)-piperidineof the formula: ##STR53## or a salt thereof.
 9. A composition for thetreatment of diseases which are characterized by disorders of theserotoninergic and dopaminergic system comprising an amount effectivetherefor of a compound or salt thereof according to claim 1 and apharmacologically acceptable diluent.
 10. A method of treating diseaseswhich are characterized by disorders of the serotoninergic anddopaminergic system in a patient in need thereof which comprisesadministering to such patient an amount effective therefor of a compoundor a salt thereof according to claim
 1. 11. A pharmaceutical compositioncomprising a therapeutically effective amount of a compound or saltthereof according to claim 2 and a pharmacologically acceptable diluent.12. A method of treating anxiety in a patient in need thereof whichcomprises administering to such patient an amount effective therefor ofa compound or salt thereof according to claim
 2. 13. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundor salt thereof according to claim 8 and a pharmacologically acceptablediluent.
 14. A method of treating anxiety in a patient in need thereofwhich comprises administering to such patient an amount effectivetherefor of a compound or salt thereof according to claim 8.